MEDICATION SAFETY

Editors: Michael Woodward, Director, Aged and Residential Care Research, Mary Britton, Consultant Geriatrician,
Rohan Elliott, Clinical Pharmacist, Graeme Vernon, Senior Drug Information Pharmacist, Austin Health; and Robyn
Saunders, Consultant Pharmacist, Victoria.
GERIATRIC THERAPEUTICS
Cardiovascular Risk Reduction in the Extreme Elderly
Seema Parikh, Kerith Sharkey, Barbara Workman
Seema Parikh, MBBS, FRACP, MPH, Academic Geriatrician, Monash Ageing
Research Centre, School of Public Health and Preventive Medicine, Monash
University; Consultant Geriatrician, Cauleld General Medical Centre; Senior
Lecturer, Faculty of Medicine, Nursing and Health Sciences, Monash University,
Kerith Sharkey, BA, BSc (Hons), MSocHlth (Eth), Manager, Monash Ageing
Research Centre, School of Public Health and Preventive Medicine, Monash
University, Barbara Workman, MBBS, FRACP, MD, AFRACMA, Medical
Director, Rehabilitation and Aged Services, Monash Health; Director, Monash
Ageing Research Centre, School of Public Health and Preventive Medicine,
Monash University; Professor of Geriatric Medicine, Faculty of Medicine,
Nursing and Health Sciences, Monash University, Clayton, Victoria
Corresponding author: Dr Seema Parikh, Monash Ageing Research Centre,
Kingston Centre, Cheltenham Vic. 3192, Australia.
E-mail: Seema.Parikh@southernhealth.org.au
ABSTRACT
An American Heart Association statement on secondary
prevention of coronary heart disease in the elderly reported
that 50% of women and 70% to 80% of men over 75 years
have obstructive coronary artery disease. The total direct and
indirect costs of cardiovascular disease and stroke in the US for
2007 was around $286 billion and annual costs are projected
to rise to over $1 trillion by 2030. Signicant emphasis is
now placed on prevention and risk factor modication of
cardiovascular disease. The proportion of the population
aged 85 years and older (the extreme elderly) is projected to
increase to 151% by 2030. This review focuses on reducing
risk in coronary heart disease and congestive heart failure in
the extreme elderly. We review modiable cardiovascular risk
factors (hypertension, lipid prole, lifestyle modication),
pharmacological strategies (statins, beta-blockers,
angiotensin converting enzyme inhibitors, angiotensin II
receptor blockers, aspirin) and the available evidence for
their use in extreme old age. There is insufcient evidence to
reach major conclusions with respect to cardiovascular risk
reduction in the extreme elderly. Further trials involving older
patients are needed before evidence-based recommendations
can be formulated for this population.
J Pharm Pract Res 2013; 43: 62-8.
INTRODUCTION
During 2007-08, around 3.5 million Australians had
cardiovascular disease (CVD), which was responsible for
34% of all deaths.
1
CVD was the most expensive chronic
disease in Australia, costing $5.9 billion in 2004-05.
1

An American Heart Association statement on secondary
prevention of coronary heart disease in the elderly reported
that 50% of women and 70% to 80% of men over 75 years
have obstructive coronary artery disease.
2
The total direct
and indirect costs of CVD and stroke in the US for 2007
was around $286 billion and annual costs are projected
to rise to over $1 trillion by 2030.
3
Signicant emphasis
is now placed on prevention and risk factor modication
of CVD.
The impact of CVD is greatest in the older person
where hospitalisation and death rates are usually the
highest.
1
CVD may be dened as all diseases and
conditions of the heart and blood vessels. Although these
include coronary heart disease, stroke, congestive heart
failure (CHF), cardiomyopathy, hypertension, peripheral
vascular disease and rheumatic heart disease, this review
focuses on reducing risk in coronary heart disease and
CHF in the extreme elderly.
Age is an independent risk factor for CVD and ageing
is associated with an increasing prevalence of coronary
artery disease, heart failure and cerebrovascular disease.
The prevalence of CVD in Australia for those over 75
years is estimated to be 62%, and coronary heart disease
is estimated to be present in 15% of females aged 75 to
84 years and 22% of females over 85 years with a higher
prevalence in males: 23% and 28% respectively.
1
Although
the prevalence of CHF is decreasing due to improvements
in the treatment of hypertension and CVD, it remains a
major morbidity for older people.
4
Traditionally, the elderly have been dened as those
aged 65 years and older, which is reected in multiple
domains of society, policy and economics. In healthcare
literature, references to the elderly can range from those
aged 60 years up to 100 years. The signicant heterogeneity
in function, cognition and medical complexity across
this age range may not be apparent. With ageing, there
is higher prevalence of functional decline, sensory
impairment, frailty, cognitive impairment and multi-
morbidity that can dene the young old (< 85 years) and
the old old ( 85 years) as two distinct populations. The
proportion of the population aged 85 years and older (the
extreme elderly) is projected to increase to 151% by
2030.
5
Given the contemporary focus on evidence-based
medicine to guide clinical decision making, it is essential
to evaluate the available literature in adults 85 years and
older, as clinicians will be increasingly challenged to
make therapeutic decisions in this population.
Risk reduction in CVD includes nutritional,
interventional and pharmaceutical domains. While
strategies such as revascularisation and glycaemic control
in diabetics are important for reducing risk, they are
beyond the scope of this review. We review modiable
cardiovascular risk factors, pharmacological strategies
and the available evidence for their use in extreme old age.
MODIFIABLE RISK FACTORS
Hypertension
The prevalence of hypertension is reported to be 74%
in people aged 80 years and older.
6
There is evidence of
benets from lowering blood pressure in middle-aged and
elderly people.
7
A meta-analysis reported systolic blood
pressure reduction to between 140 and 150 mmHg had
mortality and morbidity benets for people aged 75 years
and older.
8
However, very low blood pressure is associated
with mortality in the elderly. Observational data from a
62 Journal of Pharmacy Practice and Research Volume 43, No. 1, 2013.
Journal of Pharmacy Practice and Research Volume 43, No. 1, 2013. 63
cohort of 331 hospitalised subjects aged 70+ years (mean
85 7) support a j-shaped curve relationship with low
diastolic blood pressure ( 60 mmHg) associated with
increased all-cause death and cardiovascular death. The
study also found an inverse linear relationship between
systolic blood pressure and cardiovascular mortality.
9
While many studies focus on outcomes for control
of hypertension in those aged 60+ years, few examine
outcomes in extreme old age. The randomised controlled
Hypertension in the Very Elderly Trial (HYVET) included
3845 patients from three continents, aged 80 to 105 years,
with sustained systolic blood pressure of 160 mmHg
or more. Indapamide or a matching placebo was given
to reduce blood pressure and perindopril or a matching
placebo was added if necessary to achieve the target blood
pressure of 150 mmHg. The primary endpoint was fatal or
non-fatal stroke. After a median follow-up of 1.8 years the
study was prematurely terminated because ongoing use
of placebo was noted to be dangerous. Active treatment
was associated with a 30% reduction in fatal or non-fatal
stroke and in decompensated heart failure. The benets of
treatment became apparent within the rst year.
10
A meta-analysis which included the HYVET and
pilot HYVET data evaluated antihypertensive therapy
compared with placebo in patients aged 80 years and older
with the primary outcome of total mortality. This analysis,
which included 6701 patients from eight trials concluded
antihypertensive therapy signicantly reduced the risk
of stroke (35%), cardiovascular events (27%) and heart
failure (50%); there was no effect on total mortality.
11
The Blood Pressure Lowering Treatment Trialists
Collaboration examined 31 trials with over 190 000
participants and compared patients below 65 years (n =
96 466) with those 65 years and older (n = 94 140). They
concluded there were no signicant differences in major
cardiovascular outcomes and the benets of angiotensin
converting enzyme (ACE) inhibitors, calcium channel
blockers, diuretics or beta-blockers to lower blood pressure
are largely comparable across the age groups.
12
However,
they acknowledged the relative paucity of data for those
aged over 80 years and less than 50 years.
12
A previous
non-age specic meta-analysis by the Blood Pressure
Lowering Treatment Trialists Collaboration conrmed
treatment with any commonly-used regimen reduces the
risk of total major cardiovascular events, and that larger
reductions in blood pressure produce larger reductions in
risk.
13

Draft guidelines for hypertension from the National
Institute of Clinical Excellence recommend a target clinic
blood pressure below 150/90 mmHg in people aged 80+
years with treated hypertension, incorporating data from
HYVET.
14
However, treatment may be limited by postural
hypotension, falls, postprandial hypotension, electrolyte
disturbances and renal impairmentoutweighing the
benets of aggressive hypertension control.
Lipid Prole
Current Australian Pharmaceutical Benets Scheme
guidelines regarding eligibility for lipid lowering
treatment include a total cholesterol level of greater
than 5.5 mmol/L to less than 9 mmol/L, depending on
concurrent risk factors and subgroup populations.
15
It is
unclear whether hypercholesterolaemia is a cardiovascular
risk factor in extreme old age. A review of observational
studies on cholesterol and mortality in the 80+ age group
demonstrated a trend where all-cause mortality was
highest when total cholesterol was lowest. The authors
concluded that low total cholesterol level (< 5.5 mmol/L)
was associated with the highest mortality rate in people
aged 80 years and older.
16
With regard to CVD-specic
mortality among those 80 years and older, results varied
from nding total cholesterol associated positively and
negatively, or not at all. Similarly, the association between
high-density lipoprotein, low-density lipoprotein and total
mortality was inconclusive in observational studies.
16

Interpretation of these studies is difcult and lipid proles
may need to be viewed in the context of nutritional state,
clinical examination and comorbidities.
Lifestyle Modication
Lifestyle modications to reduce risk of CVD include
dietary changes, exercise and smoking cessation. Lifestyle
behavioural modications for mid-life adults have been
recommended and aggressively marketed, but there is
little reference to the extreme elderly due to lack of data.
Dietary Changes
Despite limited evidence for dietary changes in the 80+ age
group, recommendations can be made for consumption of
low levels of saturated fat, low salt intake (in the presence
of hypertension and/or CHF) and weight loss to aim
for a body mass index less than 30.
7
Centenarians are
considered the best example of successful cardiovascular
ageing, with a lower incidence of CVD.
17
Several reports
have documented that centenarians have followed a
series of good habits initiated at a young age. Caloric
restriction, moderate intake of alcohol and abundant intake
of vegetables rich in antioxidants correlate positively with
longevity in genetically predisposed individuals.
18
Exercise
The relationship between exercise and cardiovascular risk
reduction has not been well studied in the extreme elderly.
The level of exercise is often limited by musculoskeletal
comorbidities, cognitive issues and concurrent cardio-
respiratory disease. There are benets of exercise with
regard to fall prevention, osteoporosis and quality of life,
regardless of the direct relationship to CVD.
19,20
Smoking Cessation
Almost 10% of adults aged 65+ years are smokers and
50% of smokers will die from tobacco-related illness.
21

The benets of smoking cessation in CVD are almost
immediate, with signicant improvements in blood
pressure and heart rate within 24 hours of cessation.
Within 1 year of abstinence, the risk of cardiovascular
events such as myocardial infarction (MI) and stroke
reduce by half (compared with continued smoking).
22
Risk
reduction of MI post smoking cessation applies to younger
(25 to 49 years) and older (50 to 64 years) populations.
23

There are few studies on smoking cessation rates in old
age (particularly in those 70+ years).
24
Smoking cessation strategies include behavioural
approaches and pharmacotherapy. No clinical trials
focusing on smoking cessation strategies or outcomes in
the elderly are available. Nicotine replacement therapy
(NRT) is the most widely used form of pharmacotherapy
and includes transdermal patches, nasal spray, gum,
lozenges and nicotine inhalers.
25
NRT was found to be
effective when compared with placebo; these studies
excluded participants 65+ years.
64 Journal of Pharmacy Practice and Research Volume 43, No. 1, 2013.
Some psychotherapeutic drugs, such as bupropion,
clonidine and nortriptyline have also been studied; age
range of patients included in these trials was 18 to 70
years. Smoking cessation rates at 1 year were better with
varenicline (a nicotinic acetylcholine receptor partial
agonist) (23%) than bupropion (15%) or placebo (10%);
age range examined was 18 to 75 years. The US Food
and Drug Administration has advised that varenicline
may be associated with a small increased risk of certain
cardiovascular events in patients who have cardiovascular
disease after a trial involving 700 people with CVD was
completed. While these events did not reach statistical
signicance, they invite further investigation.
26
Although
there is little direct evidence for individual strategies in
patients aged 85 years and older, the benets of smoking
cessation are clear up to the age of 75 years.
PHARMACOLOGY
Statins
The role of statins in lowering lipids has been well
established. However, their role in cardiovascular risk
reduction independent of their effect on cholesterol
through improving endothelial function is of recent
interest.
27
Multiple randomised controlled trials have
conrmed the benet of statins in middle-aged adults
including cholesterol reduction and secondary prevention
of further cardiovascular events.
A few studies examining cardiovascular risk have
included participants aged 80+ years.
16
The randomised
controlled PROSpective study of Pravastatin in Elderly
individuals at Risk (PROSPER) examined the benet of
pravastatin in an elderly cohort of men and women with a
high risk of developing CVD and stroke. Participants were
aged 70 to 82 years and were followed for 3.2 years with
a primary endpoint which was a composite of coronary
death, non-fatal MI and fatal or non-fatal stroke. The
authors concluded that pravastatin for 3 years reduced
coronary heart disease in the elderly. The primary endpoint
was reduced by 23% in men but only 4% in women.
28
The
trial did not include patients of extreme old age, so there
remains a gap in the evidence for this age group.
Another randomised controlled trial studied
rosuvastatin in older patients with systolic heart failure
of ischaemic cause examining the primary composite
outcome of death from cardiovascular causes, non-fatal
MI or non-fatal stroke. Over 41% of the 5011 participants
were aged 75+ years. A subgroup analysis examined
patients aged 77+ years. The primary outcome was not
signicantly different between the two groups but there
was a reduction in cardiac hospitalisations in the group
treated with rosuvastatin.
29

No prospective trials have examined statin efcacy
in adults of extreme age exclusively. A recent Cochrane
review examining statins in primary prevention of CVD
reported reductions in all-cause mortality, major vascular
events and revascularisations in people without evidence
of cardiac disease.
30
However, age-specic analyses were
abandoned due to lack of adequate data. A meta-analysis
of nine trials encompassing 19 569 patients with an
age range of 65 to 82 years with coronary heart disease
reported a reduction in mortality, non-fatal MI, need for
revascularisation and stroke.
31
An observational cohort
study of 14 907 post-MI patients aged 80 years and older
reported lower cardiovascular mortality in those receiving
statins at discharge.
32
There is insufcient primary evidence to recommend
initiating or continuing statins in those aged 85 years and
older.
30
No clinical trials have been designed to address
primary and secondary prevention of coronary events in
the extreme elderly using statins.
33
Beta-Blockers
Beta-blockers are used in acute coronary syndromes,
hypertension, stable angina and CHF. The role of beta-
blockers in CHF will be discussed given prevalence
rises sharply with age (over 10% in those aged 80 years
and older).
34
The median age of presentation of CHF is
75 years.
34
Concerns regarding tolerability and relative
efcacy of beta-blockers in extreme old age have
been raised due to comorbidities, frailty and declining
functional abilities.
35
Several useful properties of beta-
blockers may account for their benecial role in CHF:
reduce adrenergic drive, improve autonomic balance
and reduce heart wall stress.
36
A systematic review of 22
randomised controlled trials reported that beta-blockers
reduced hospital admissions and risk of death in patients
with a low ejection fraction.
37
While the mean age of the
predominantly male population was 61 years, it provides
some evidence supporting the use of beta-blockers in
older people.
37

The Study of the Effects of Nebivolol in Outcomes
and Rehospitalization in Seniors with Heart Failure
(SENIORS) evaluated a beta-blocker in patients aged 70
years and older (n = 2128) regardless of ejection fraction;
mean age of participants was 76 years (range 6995).
38
The
primary outcome was a composite of all-cause mortality
or cardiovascular hospital admission (time to rst event).
The proportion of patients who suffered the primary
outcome in the nebivolol group was 31% compared with
35% in the placebo group (HR 0.9; 95%CI 0.71.0) a
statistically signicant difference. A subgroup analysis
did not reveal signicant differences for patients aged 75+
years. Nebivolol was well tolerated in all age groups.
Two major trials reported the benet of carvedilol in
heart failure. The randomised controlled Carvedilol or
Metoprolol European Trial (COMET) compared carvedilol
with metoprolol; the mean age of the study population
was 62 years.
39
Some data were presented for participants
under 65 years and over 65 years; no conclusion can be
reached for the extreme elderly. Similarly, the randomised,
double-blind, placebo-controlled Carvedilol Prospective
Randomized Cumulative Survival Study Group
(COPERNICUS) trial investigated carvedilol in addition
to standard heart failure treatment in 2289 patients with
moderate to severe heart failure with an ejection fraction
less than 25%; mean age of participants was 63 years.
40

Subgroup analyses were presented for several parameters,
such as age. The reduction in mortality and combined risk
of death or hospitalisation favoured cardvedilol. However,
the elderly subgroups identied were aged 65+ years and
the size of the benet appeared to be quantitatively smaller
in this age group. Therefore, applying these results to those
of extreme age may be difcult. Retrospective analyses of
the Metoprolol CR/XL Randomized Intervention trial in
Heart Failure (MERIT-HF) of elderly patients aged 65+
years examined efcacy, safety and tolerability. Although
patients aged 75+ years were studied, the oldest patients
were 80 years of age.
41
This analysis reported metoprolol
CR/XL was easily instituted, safe and well tolerated when
initiating therapy and long-term follow-up in the elderly
with systolic heart failure.
41
There is weak evidence of benet for using beta-
blockers in CHF in the extreme elderly. These should be used
cautiously to ensure tolerability. Careful patient selection
and close monitoring are essential to minimise risks. In
the Cardiovascular Health Study, 18% of community-
dwelling older adults had orthostatic hypotension.
42

The American College of Cardiology and the American
Heart Association guidelines recommend beta-blockers
in all chronic systolic heart failure patients unless there
is a history of intolerance or a contraindication.
43
Beta-
blockers should be commenced at low doses and titrated
accordingly.
43
The impact on heart rate, blood pressure
and symptomatic dizziness need attention in relation
to functional status. Concurrent medications must be
considered in the decision to prescribe beta-blockers. For
example, those on small doses of ACE inhibitors may
tolerate beta-blockers well.
44

Data for beta blockade in those aged 80 years and older
post-MI are limited. The Cardiovascular Co-operative
Project reviewed over 200 000 records and reported that
mortality was 32% lower in patients aged 80 years and
older who received beta blockade post-MI.
45
Prospective
trial data in this age group are not available.
Angiotensin Converting Enzyme Inhibition
ACE inhibitors and angiotensin II receptor blockers
(ARBs) have been studied in heart failure, ischaemic
heart disease and stroke. However, only a few trials have
included patients of extreme old age. Table 1 displays
major clinical trials which included older participants.
Of note, GISSI-3 had 27% of subjects over 70 years of
age.
46
The absolute reduction for a combined mortality
and cardiovascular endpoint in the elderly participants
was 3.5%. The non-age specic mortality reduction for
the other trials was 4% to 6%. EUROPA, ISIS-4, Val-Heft
and OPTIMAAL presented subgroup analyses of patients
65 years and older with similar results to the younger
counterparts.
47-50
A post hoc analysis from the HOPE
study was later published evaluating 2755 patients aged
70 years and older.
51
Those assigned to ramipril had fewer
major vascular events compared to placebo. Furthermore,
ramipril was safe and well tolerated.
34
A meta-analysis of 32 randomised clinical trials has
demonstrated the effectiveness of ACE inhibitors for
reducing morbidity and mortality in heart failure. The
benets are similar for patients over 80 years and 60
years and younger.
52
A retrospective cohort study of frail
elderly patients (mean age 85 years) reported that patients
Table 1. Trials of angiotensin converting enzyme inhibition that included older people
Study Drug Population
Patients 85
years Primary outcome Results
CONSENSUS Enalapril vs placebo CHF NYHA IV Yes All-cause mortality Signicant decrease in
mortality at 6 and 12 months
GISSI-3 Lisinopril vs placebo Post-MI and CHF Yes All-cause mortality
LV dysfunction
Decrease in 6-week
mortality; decreased rate of
composite endpoint of death
and late-onset heart failure
ISIS-4 Captopril vs placebo Post-MI and CHF All-cause mortality Signicant reduction in
mortality at 5 weeks
HOPE Ramipril vs placebo CV disease or diabetes
and/or one other CV risk
factor
Yes, n = 9297 Composite endpoint
of MI, stroke or CV
death
Decreased mortality, MI,
stroke in broad age range
PROGRESS Perindopril
indapamide vs
placebo
Prior stroke or TIA
within 5 years
Yes Stroke Decreased risk of recurrent
stroke
ALLHAT Lisinopril vs
chlorthalidone vs
amlodipine
Hypertension and one
CV risk factor
Yes, > 100
years
Combined fatal CHD
or non-fatal MI
No signicant decrease in
primary outcome
EUROPA Perindopril vs
placebo
CHD Yes, up to 90
years
Composite endpoint
of CV death, MI or
cardiac arrest
Treatment group had fewer
CV events
PEACE Trandolapril vs
placebo
Stable CAD and normal
or mildly reduced LV
function
Unclear, n =
912 75 years
Death CV causes,
MI/cardiac
revascularisation
No signicant decrease in
primary outcome
Val-Heft Valsartan vs placebo CHF NYHA II-IV Yes Mortality or
combined mortality
and morbidity
Decreased morbidity and
mortality; benecial effect
seen in those aged > 65 years
OPTIMAAL Losartan vs captopril Acute MI and CHF Yes All-cause mortality Non-signicant difference in
total mortality
VALIANT Valsartan vs captopril
vs both
Acute MI and CHF Yes All-cause mortality Main outcome did not differ
between treatment groups
SCOPE Candesartan vs
placebo
Hypertension Yes, 70-89
years, 80
(21%) years
Composite endpoint
of CV death, non-
fatal stroke/MI
Slightly more effective
blood pressure reduction
with candesartan
VALUE Valsartan vs
amlodipine
Hypertension and CV
risk
Yes Cardiac event No difference in endpoint
CAD = coronary artery disease. CHD = coronary heart disease. CHF = congestive heart failure. CV = cardiovascular. LV = left ventricular.
MI = myocardial infarction. NHYA = New York Heart Association. TIA = transient ischaemic attack.
Journal of Pharmacy Practice and Research Volume 43, No. 1, 2013. 65
receiving ACE inhibitors had 10% reduction in mortality
and a lower rate of functional decline. Data suggested
survival and functional benets of ACE inhibitor therapy
in CHF pertains to patients aged s85 years and older.
53
A systematic review reported the comparative
effectiveness of ACE inhibitors or ARBs for ischaemic
heart disease.
54
After examining 41 randomised controlled
trials, the authors concluded: adding an ACE inhibitor to
standard medical therapy improves outcomes, including
reduced risk for mortality and MI, in some patients with
stable IHD and preserved ventricular failure. Less evidence
supports a benet of ARB therapy, and combination
therapy seems no better than ACE inhibitor therapy alone
and increases harms.
54
The analysis was not age specic.
Although ACE inhibition is an important element
of cardiac risk reduction, it needs to be balanced
with potential adverse reactions, such as orthostatic
hypotension, falls and renal impairment. Alternatively,
a retrospective review of 295 hospitalised older patients
reported signicant survival benet for those on ACE
inhibitors with perceived contraindications, such as
hypotension, renal insufciency or severe aortic stenosis.
44

Although the study was retrospective and had a small
study population, it illustrates benets at older age. Patient
function, cognition and other domains must be considered
when prescribing; adopting a conservative approach to
dosing while actively titrating.
Aspirin
Primary Prevention
A meta-analysis of randomised controlled trials examining
the effect of aspirin on vascular and non-vascular outcomes
reported that aspirin reduced cardiovascular events by 10%
primarily by reducing non-fatal MI in primary prevention.
In contrast, there was a 70% excess risk of total bleeding
events (OR 1.7; 95%CI 1.22.5) and a higher than 30%
excess risk of non-trivial bleeding events (OR 1.3; 95%CI
1.11.5) in people receiving aspirin; mean age was 57
years (SD 4.1). A non-signicant increase in the risk of
haemorrhagic stroke of about one-third was observed in
this meta-analysis.
55
There are some data for patients aged 70+ years,
suggesting benets outweigh the risks, but the data
are less clear than in younger age groups.
56
Of nine
randomised controlled trials evaluating aspirin in primary
prevention of cardiovascular events, eight trials included
patients aged 70+ years. Results of subgroup analyses for
older participants were reported in six of these trials.
57
The
Physicians Health Study reported signicant reduction in
MI in these age groups; the Primary Prevention Project
showed a non-signicant increase in coronary deaths for
the older age group; while the Womens Health Study
reported reduced risk of ischaemic stroke and MI for those
aged 65+ years. The role of aspirin in primary prevention
remains to be established.
57-60
A primary prevention randomised, double-blind,
placebo-controlled trial, ASPirin in Reducing Events
in the Elderly (ASPREE) is in progress, assessing the
effect of enteric-coated aspirin 100 mg daily on duration
of disability-free survival in healthy participants aged
70 years and older. The study will recruit over 19 000
participants in Australia and the USA.
61
Secondary Prevention
The efcacy of aspirin in occlusive CVD has long been
established in a number of populations through its anti-
platelet properties.
62
However, at high doses aspirin has
been postulated to have other biological mechanisms that
may decrease the risks of CVD, such as reducing elevated
levels of inammatory markers, e.g. pro-inammatory
cytokines, C-reactive proteins. The use of aspirin in
extreme old age has not been well studied. In older patients
(including 85 years) with established CVD, such as
coronary artery disease and cerebrovascular disease,
low-dose aspirin reduced the risk of further vascular
events, non-fatal stroke, non-fatal MI and vascular
death.
63,64
However, concern about gastrointestinal
tolerability, especially bleeding, exists due to concurrent
multi-morbidity. Greater vigilance and consideration of
comorbidities, as well as cognitive and functional status
may be required.
DISCUSSION
The paucity of published cardiology trials which include
patients of extreme old age has been reported previously.
Gurwitz et al.
65
searched the literature (January 1966 to
September 1991) to identify drug trials in acute MI and
of the 214 trials, more than 60% excluded patients over
75 years. The bulk of literature in the elderly continues
to report on those aged 65 years and older, however
subgroup analyses are being presented more frequently,
as increasing lifespan is acknowledged. Some evidence is
available for the extreme elderly in cardiac risk reduction
but the evidence base is sparse when compared to all
available literature.
There are difculties conducting clinical research
in the extreme elderly. Patient recruitment remains a
challenge as comorbidities limit their inclusion in trials.
Clinical drug trials often involve numerous visits to
hospital for investigations, which can impact on an older
persons ability to comply with study requirements.
66

Issues of cognitive impairment and capacity to consent
can also present ethical dilemmas. There are implications
for resource allocation and preventive medical services
if we do not know the effect of interventions in the
extreme elderly, especially in the context of an ageing
population. Trials must attempt to enrol participants more
representative of older populations.
Goals of care of the extreme elderly must also be
considered on an individual basis. At this extreme end
of the age spectrum, patients wishes and life satisfaction
need to be acknowledged. Interventions that have an
immediate effect on wellbeing may be more important
than preventing future illness. A longitudinal population
study of individuals aged 78 to 98 years found diagnoses,
such as stroke, dementia and cardiac disease were not
related to life satisfaction. Alternatively, depressive mood
and number of symptoms were signicant predictors of
poor life satisfaction at 3 years.
67
Underutilisation of preventive and treatment measures
addressing chronic disease has been documented in older
populations.
68
Clinicians may be reluctant to initiate
medications because of the risks of polypharmacy
and increasing the risk of falls, cognitive decline and
various geriatric syndromes.
69
Medication adherence also
needs to be considered when prescribing and patient-
friendly dosing regimens formulated. Clinicians need
to incorporate a comprehensive assessment of function,
cognition, comorbidities and goals of care into decision
making for cardiac prevention.
66 Journal of Pharmacy Practice and Research Volume 43, No. 1, 2013.
Journal of Pharmacy Practice and Research Volume 43, No. 1, 2013. 67
In conclusion, there is insufcient evidence to reach
major conclusions with respect to cardiac risk reduction in
the extreme elderly. Further trials involving older patients
are needed before evidence-based recommendations can
be formulated for this population.
Competing interests: None declared
References
1. Australian Institute of Health and Welfare. Cardiovascular disease:
Australian facts 2011. Cardiovascular disease series. Cat. no. CVD 53.
Canberra: Australian Institute of Health and Welfare; 2011.
2. Williams MA, Fleg JL, Ades PA, Chaitman BR, Miller NH, Mohiuddin
SM, et al. Secondary prevention of coronary heart disease in the elderly (with
emphasis on patients > or =75 years of age): an American Heart Association
scientic statement from the Council on Clinical Cardiology Subcommittee
on Exercise, Cardiac Rehabilitation, and Prevention. Circulation 2002; 105:
1735-43.
3. Weintraub WS, Daniels SR, Burke LE, Franklin BA, Goff DC Jr, Hayman
LL, et al. Value of primordial and primary prevention for cardiovascular
disease: a policy statement from the American Heart Association. Circulation
2011; 124: 967-90.
4. Curtis LH, Whellan DJ, Hammill BG, Hernandez AF, Anstrom KJ, Shea
AM, et al. Incidence and prevalence of heart failure in elderly persons, 1994-
2003. Arch Intern Med 2008; 168: 418-24.
5. United Nations Department of Economic and Social Affairs, Population
Division. World population prospects: the 2004 revision. New York: United
Nations; 2005.
6. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age
spectrum: current outcomes and control in the community. JAMA 2005; 294:
466-72.
7. Bulpitt CJ. Secondary prevention of coronary heart disease in the elderly.
Heart 2005; 91: 396-400.
8. Schall P, Wehling M. Treatment of arterial hypertension in the very elderly: a
meta-analysis of clinical trials. Arzneimittelforschung 2011; 61: 221-8.
9. Protogerou AD, Safar ME, Iaria P, Safar H, Le Dudal K, Filipovsky J, et
al. Diastolic blood pressure and mortality in the elderly with cardiovascular
disease. Hypertension 2007; 50: 172-80.
10. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al.
Treatment of hypertension in patients 80 years of age or older. N Engl J Med
2008; 358: 1887-98.
11. Bejan-Angoulvant T, Saadatian-Elahi M, Wright JM, Schron EB, Lindholm
LH, Fagard R, et al. Treatment of hypertension in patients 80 years and
older: the lower the better? A meta-analysis of randomized controlled trials. J
Hypertens 2010; 28: 1366-72.
12. Turnbull F, Neal B, Ninomiya T, Algert C, Arima H, Barzi F, et al. Effects
of different regimens to lower blood pressure on major cardiovascular events
in older and younger adults: meta-analysis of randomised trials. BMJ 2008;
336: 1121-3.
13. Turnbull F. Effects of different blood-pressure-lowering regimens on
major cardiovascular events: results of prospectively-designed overviews of
randomised trials. Lancet 2003; 362: 1527-35.
14. National Institute for Health and Clinical Excellence. Clinical management
of primary hypertension in adults. NICE clinical guideline 127. London:
National Institute for Health and Clinical Excellence; 2011. Available from
<www.guidance.nice.org.uk/cg127>.
15. Department of Health and Ageing. General statement for lipid-lowering
drugs prescribed as pharmaceutical benets. Canberra: Department of Health
and Ageing. Available from <www.pbs.gov.au/info/healthpro/explanatory-
notes/gs-lipid-lowering-drugs>.
16. Petersen LK, Christensen K, Kragstrup J. Lipid-lowering treatment to the
end? A review of observational studies and RCTs on cholesterol and mortality
in 80+-year olds. Age Ageing 2010; 39: 674-80.
17. Galioto A, Dominguez LJ, Pineo A, Ferlisi A, Putignano E, Belvedere M, et
al. Cardiovascular risk factors in centenarians. Exp Gerontol 2008; 43: 106-13.
18. Perls T, Terry D. Understanding the determinants of exceptional longevity.
Ann Intern Med 2003; 139: 445-9.
19. Maciaszek J, Osinski W. Effect of tai chi on body balance: randomized
controlled trial in elderly men with dizziness. Am J Chin Med 2012; 40: 245-53.
20. McNamara A, Gunter K. The inuence of participation in Better Bones and
Balance on skeletal health: evaluation of a community-based exercise program
to reduce fall and fracture risk. Osteoporos Int 2011; 23: 1813-22.
21. Appel DW, Aldrich TK. Smoking cessation in the elderly. Clin Geriatr Med
2003; 19: 77-100.
22. US Department of Health and Human Services. The health benets of
smoking cessation: a report of the Surgeon General. Rockville: US Public
Health Service, Ofce on Smoking and Health; 1990.
23. Rosenberg L, Palmer JR, Shapiro S. Decline in the risk of myocardial
infarction among women who stop smoking. N Engl J Med 1990; 322: 213-17.
24. Connolly MJ. Smoking cessation in old age: closing the stable door? Age
Ageing 2000; 29: 193-5.
25. Henningeld JE, Fant RV, Buchhalter AR, Stitzer ML. Pharmacotherapy
for nicotine dependence. CA Cancer J Clin 2005; 55: 281-99.
26. US Food and Drug Administration. FDA drug safety communication:
Chantix (varenicline) may increase the risk of certain cardiovascular adverse
events in patients with cardiovascular disease. Silver Spring: US Food and
Drug Administration; 2011. Available from <www.fda.gov/Drugs/DrugSafety/
ucm259161.htm>.
27. Wolfrum S, Jensen KS, Liao JK. Endothelium dependent effects of statins.
Arterioscler Thromb Vasc Biol 2003; 23: 729-36.
28. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM,
et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER):
a randomised controlled trial. Lancet 2002; 360: 1623-30.
29. Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, Cornel JH, et al.
Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;
357: 2248-61.
30. Taylor F, Ward K, Moore TH, Burke M, Davey Smith G, Casas JP, et
al. Statins for the primary prevention of cardiovascular disease. Cochrane
Database Syst Rev 2011; Issue 1. Art. No.: CD004816.
31. Alalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ.
Statins for secondary prevention in elderly patients: a hierarchical bayesian
meta-analysis. J Am Coll Cardiol. 2008; 51: 37-45.
32. Gransbo K, Melander O, Wallentin L, Lindback J, Stenestrand U, Carlsson
J, et al. Cardiovascular and cancer mortality in very elderly post-myocardial
infarction patients receiving statin treatment. J Am Coll Cardiol 2010; 55:
1362-9.
33. Alonzo CB. Myths and facts concerning the use of statins in very old
patients. Cardiovasc Hematol Disord Drug Targets 2011; 11: 17-23.
34. Coats AJ. Beta-adrenoceptor antagonists in elderly patients with chronic
heart failure: therapeutic potential of third-generation agents. Drugs Aging
2006; 23: 93-9.
35. Yanagisawa S, Suzuki N, Tanaka T. Poor tolerance of beta-blockers by
elderly patients with heart failure. Clin Interv Aging 2010; 5: 365-8.
36. Rousseau MF, Chapelle F, Van Eyll C, Stoleru L, Hager D, Van Nueten
L, et al. Medium-term effects of beta-blockade on left ventricular mechanics:
a double-blind, placebo-controlled comparison of nebivolol and atenolol in
patients with ischemic left ventricular dysfunction. J Card Fail 1996; 2: 15-23.
37. Shibata MC, Flather MD, Wang D. Systematic review of the impact of beta
blockers on mortality and hospital admissions in heart failure. Eur J Heart Fail
2001; 3: 351-7.
38. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko
A, Borbola J, et al. Randomized trial to determine the effect of nebivolol on
mortality and cardiovascular hospital admission in elderly patients with heart
failure (SENIORS). Eur Heart J 2005; 26: 215-25.
39. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P,
Komajda M, et al. Comparison of carvedilol and metoprolol on clinical
outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol
European Trial (COMET): randomised controlled trial. Lancet 2003; 362: 7-13.
40. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al.
Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med
2001; 344: 1651-8.
41. Deedwania PC, Gottlieb S, Ghali JK, Waagstein F, Wikstrand JC. Efcacy,
safety and tolerability of beta-adrenergic blockade with metoprolol CR/XL in
elderly patients with heart failure. Eur Heart J 2004; 25: 1300-9.
42. Rutan GH, Hermanson B, Bild DE, Kittner SJ, LaBaw F, Tell GS.
Orthostatic hypotension in older adults: the cardiovascular health study.
Hypertension 1992; 19: 508-19.
43. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats
TG, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and
management of heart failure in adults: a report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines: developed in collaboration with the International Society for Heart
and Lung Transplantation. Circulation 2009; 119: 1977-2016.
44. Ahmed A, Kiefe CI, Allman RM, Sims RV, DeLong JF. Survival benets
of angiotensin-converting enzyme inhibitors in older heart failure patients with
perceived contraindications. J Am Geriatr Soc 2002; 50: 1659-66.
45. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality
among high-risk and low-risk patients after myocardial infarction. N Engl J
Med 1998; 339: 489-97.
46. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and
together on 6-week mortality and ventricular function after acute myocardial
infarction. Gruppo Italiano per lo Studio della Sopravvivenza nellinfarto
Miocardico. Lancet 1994; 343: 1115-22.
47. Fox KM; EURopean trial On reduction of cardiac events with Perindopril
in stable coronary Artery disease Investigators. Efcacy of perindopril in
reduction of cardiovascular events among patients with stable coronary artery
disease: randomised, double-blind, placebo-controlled, multicentre trial (the
EUROPA study). Lancet 2003; 362: 782-8.
48. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative
Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral
mononitrate, and intravenous magnesium sulphate in 58,050 patients with
suspected acute myocardial infarction. Lancet 1995; 345: 669-85.
49. Cohn JN, Tognoni G; for the Valsartan Heart Failure Trial Investigators. A
randomized trial of the angiotensin-receptor blocker valsartan in chronic heart
failure. N Engl J Med 2001; 345: 1667-75.
50. Dickstein K, Kjekshus J; OPTIMAAL Steering Committee of the
OPTIMAAL Study Group. Effects of losartan and captopril on mortality and
morbidity in high-risk patients after myocardial infarction: the OPTIMAAL
randomised trial. Lancet 2002; 360: 752-60.
68 Journal of Pharmacy Practice and Research Volume 43, No. 1, 2013.
51. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of
an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
events in high-risk patients. The Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med 2000; 342: 145-53.
52. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting
enzyme inhibitors on mortality and morbidity in patients with heart failure.
Collaborative Group on ACE Inhibitor Trials. JAMA 1995; 273: 1450-6.
53. Gambassi G, Lapane KL, Sgadari A, Carbonin P, Gatsonis C, Lipsitz LA,
et al. Effects of angiotensin-converting enzyme inhibitors and digoxin on
health outcomes of very old patients with heart failure. SAGE Study Group.
Systematic Assessment of Geriatric drug use via Epidemiology. Arch Intern
Med 2000; 160: 53-60.
54. Baker WL, Coleman CI, Kluger J, Reinhart KM, Talati R, Quercia R, et
al. Systematic review: comparative effectiveness of angiotensin-converting
enzyme inhibitors or angiotensin iireceptor blockers for ischemic heart
disease. Ann Intern Med 2009; 151: 861-71.
55. Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Erqou S, Sattar
N, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis
of randomized controlled trials. Arch Intern Med 2012; 172: 209-16.
56. Mahe I, Leizorovicz A, Caulin C, Bergmann JF. Aspirin for the prevention
of cardiovascular events in the elderly. Drugs Aging 2003; 20: 999-1010.
57. Ward SA, Demos L, Workman B, McNeil JJ. Aspirin for primary prevention
of cardiovascular events in the elderly: current status and future directions.
Drugs Aging 2012; 29: 251-8.
58. Final report on the aspirin component of the ongoing Physicians Health
Study. Steering Committee of the Physicians Health Study Research Group. N
Engl J Med 1989; 321: 129-35.
59. de Gaetano G; Collaborative Group of the Primary Prevention Project.
Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised
trial in general practice. Lancet 2001; 357: 89-95.
60. Ridker PM, Cook MR, Lee IM, Gordon D, Gaziano JM, Manson JE,
et al. A randomized trial of low-dose aspirin in the primary prevention of
cardiovascular disease in women. N Engl J Med 2005; 352: 1293-304.
61. Nelson M, Reid C, Beilin L, Donnan G, Johnston C, Krum H, et al. Aspirin
in Reducing Events in the Elderly (ASPREE) Study Group. Rationale for a trial
of low-dose aspirin for the primary prevention of major adverse cardiovascular
events and vascular dementia in the elderly. Drugs Aging 2003; 20: 897-903.
62. Hennekens CH. Update on aspirin in the treatment and prevention of
cardiovascular disease. Am J Manag Care 2002; 8 (22 suppl): S691-S700.
63. ISIS-2 (Second International Study of Infarct Survival) Collaborative
Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or
neither among 17,187 cases of suspected acute myocardial infarction. Lancet
1988; 2: 349-60.
64. Krumholz HM, Radford MJ, Ellerbeck EF, Hennen J, Meehan TP, Petrillo
M, et al. Aspirin in the treatment of acute myocardial infarction in elderly
Medicare beneciaries. Patterns of use and outcomes. Circulation 1995; 92:
2841-7.
65. Gurwitz JH, Col NF, Avorn J. The exclusion of the elderly and women
from clinical trials in acute myocardial infarction. JAMA 1992; 268: 1417-22.
66. Bene J, Liston R. Clinical trials should be designed to include elderly
people. BMJ 1998; 316: 1905.
67. Enkvist A, Ekstrom H, Elmstahl S. What factors affect life satisfaction (LS)
among the oldest-old? Arch Gerontol Geriatr 2012; 54: 140-5.
68. Jennings LA, Auerbach AD, Maselli J, Pekow PS, Lindenauer PK, Lee SJ.
Missed opportunities for osteoporosis treatment in patients hospitalized for hip
fracture. J Am Geriatr Soc 2010; 58: 650-7.
69. Elliott RA. Problems with medication use in the elderly: an Australian
perspective. J Pharm Pract Res 2006; 36: 58-66.
Received: 20 April 2012
Revisions requested after external review: 5 February 2013
Revised version received: 19 March 2013
Accepted: 25 March 2013
Grant Value Closing date
Auditmaker Clinical Audit Grant $5000 31 August 2013
Hospira Pharmacist Award $10 000 31 July 2013
Roche Research Grant on
Quality and Safety
$10 000 31 August 2013
Celgene Pharmacy Grant $20 000 30 September
2013
Grant schedule for 2013
SHPA Research and Development Grants
Program
In 2013 the RDGAC transitioned to Queensland and will
be in the capable hands of a group of experienced clinical
practitioners and researchers. Many thanks to the South
Australian team for their time and expertise in leading a
successful RDGAC over the past 5 years. We congratulate
Anna McClure, Joy Gailer, Sepehr Shakib, Manya Angley,
Greg Roberts, Luke Grzeskowiak, Helen Lovitt and Della
Absalom for their achievements.
The new committee includes:
Tony Hall SHPA Federal Councillor and Lecturer,
Grifth University
Dr Jason Roberts SHPA Fellow and Consultant
Pharmacist, Royal Brisbane and Womens Hospital
Arna Neilson SHPA Queensland State Branch
representative
Dr Neil Cottrell SHPA Fellow and Senior lecturer,
University of Queensland
Jo Sturtevant Consultant Pharmacist, Princess
Alexandra Hospital
Dr Peter Donovan Clinical Pharmacologist, Royal
Brisbane and Womens Hospital
Dr Michael Barras (Chair) Assistant Director of
Pharmacy, Royal Brisbane and Womens Hospital
Della Absalom Assistant to Federal Secretariat,
SHPA
The committee is privileged to retain Joy Gailer to
help guide the transition.
The rst two SHPA grants for the year have closed and
we thank all applicants. The remaining grants for 2013 are
listed, along with the respective closing dates. This year, to
compliment the Hospira Pharmacy Award and the Roche
Safety and Quality Grant, will see the re-introduction of
the Auditmaker Clinical Audit Research Grant. This grant
is aimed at a researcher with aspirations to undertake a
clinical audit using the Auditmaker software. The software
is designed to assist with multi-centre data collection and
analysis; therefore we recommend applying for funds
to support a multi-site, collaborative project. The other
major grant is the Celgene Pharmacy Grant to support
information technology in hospital pharmacy. This grant
was not awarded in 2012 and therefore $20 000 is now
available.
We encourage all pharmacists and technicians to
consider applying for one of these exciting grants. First-
time research applicants should seek the advice and
expertise of peers and/or consult with the relevant COSP
for guidance. If you have queries about the application
process, consult the SHPA web site <www.shpa.org.
au> or contact Della Absalom, Assistant to the Federal
Secretariat <dabsalom@shpa.org.au>.